Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up

We previously reported that prednisone reduced the frequency of generalized myasthenia (GMG) and controlled diplopia without major adverse effects at 2 years in patients with ocular myasthenia gravis (OMG). Questions remain as to whether study subjects had long-standing disease, biasing results towards a steroid benefit, and if prednisone merely delayed GMG onset. Here, we performed a record review of a referral neuro-ophthalmology service OMG database for patients who were followed-up for ≥4 years or until GMG developed. We studied the effect of prednisone on GMG incidence and control of ocular symptoms. Generally, patients with diplopia were recommended for prednisone therapy. Most remained on daily 2.5–10 mg for diplopia control. We compared the results for prednisone-treated and “untreated” (pyridostigmine only) patients. Of 87 patients, 55 were in the prednisone-treated and 32 were in the untreated groups. GMG developed in 7 (13%) of the prednisone-treated (OR 0.41; 95% CI 0.22–0.76) and in 16 (50%) of the untreated (OR 2.78; 95% CI 1.68–4.60) patients. After OMG onset, GMG developed at a mean 5.8 and 0.22 years in prednisone and untreated groups. Diplopia was present at the last exam in 27% of the prednisone-treated (mean 7.2 years) and in 57% of the untreated (mean 4.6 years) OMG patients. For 48 prednisone-treated patients who did not develop GMG, OMG treatment failure occurred in 13. Thus, prednisone delays the onset of GMG and has sustained benefit in reducing the incidence of GMG and controlling diplopia. Without prednisone, GMG develops in 50% of OMG patients, typically within 1 year.     

眼肌型重症肌无力临床分析

目的总结分析眼肌型重症肌无力患者的临床特征,以为诊断和治疗提供参考依据。方法回顾性分析113例眼肌型重症肌无力患者的临床资料。采用免疫荧光细胞染色方法检测血清乙酰胆碱受体(AChR)抗体和肌肉特异性受体酪氨酸激酶(MuSK)抗体表达水平,分析这两项免疫学指标对眼肌型重症肌无力向全身型转化的预测价值。结果成年发病的眼肌型重症肌无力好发于40岁以上男性,多以眼睑下垂(95例,84.07%)为首发症状,少数以复视(18例,1 5.93%)起病。疲劳试验和新斯的明试验阳性率分别为79.44%(85/107)和84.85%(84/99),低频重复神经电刺激和血清甲状腺抗体异常率分别为44.32%(39/88)和28%(14/50),胸腺增生和胸腺瘤阳性率分别为16.67%(17/102)和11.76%(12/102);血清AChR抗体阳性率为62.83%(71/113);但MuSK抗体均呈阴性。眼肌型重症肌无力向全身型转化率为12.39%(14/113),其中血清AChR抗体强阳性者(13例,28.26%)显著高于弱阳性者(1例,4%),二者差异有统计学意义(X~2=4.587,P=0.032)。结论成年发病的眼肌型重症肌无力好发于中年以上男性,主要表现为眼睑下垂和复视,大多数患者伴发胸腺和甲状腺异常。血清AChR抗体表达水平升高预示向全身型转化率升高,鲜有MuSK抗体阳性反应。     

Prognosis of ocular myasthenia in Korea: a retrospective multicenter analysis of 202 patients

OBJECTIVES: The aims of this study were to obtain data on the frequency with which Korean patients with autoimmune myasthenia gravis (MG) present solely with ocular disturbances and progress to develop generalized disease and to identify the prognostic factors associated with secondary generalization. METHODS: We conducted a retrospective multicenter survey in which a total of 376 adult patients who were newly diagnosed with MG from 2000 through 2005 were reviewed for analysis. Patients with ocular MG at the time of symptom presentation (n=202, 53.7%) were divided into two subgroups according to their prognosis: the patients whose disease remained ocular throughout the follow-ups were placed in the OMG-R group, and the patients who progressed to develop generalized disease were placed in the OMG-G group. Clinical characteristics and laboratory findings were compared between the two subgroups. RESULTS: Secondary generalization developed in 47 (23.3%) of the 202 study subjects, mostly within the first 6 months after symptom presentation, while the disease remained ocular throughout the follow-up duration (median 11.8 months) in the remaining 155 patients (76.7%). AChR antibody, abnormal repetitive nerve stimulation tests (RNST) and thymoma were more frequently observed in the patients in the OMG-G group than in those in the OMG-R group (p<0.01 in all). In seropositive cases, the titers of AChR antibody were also significantly higher in the OMG-G group than in the OMG-R group (median, 3.8 nM vs. 6.4 nM; p<0.05). Cox proportional hazards regression analyses showed that early oral prednisolone treatment significantly reduced the risk of secondary generalization (HR, 0.24; 95% CI, 0.11-0.56), whereas abnormal AChR antibody (HR, 5.34; 95% CI, 1.60-17.8) and thymoma (HR, 2.32; 95% CI, 1.21-4.45) were predictive of the development of secondary generalization. CONCLUSIONS: Our findings suggest that several factors, including the AChR antibody, thymoma, early corticosteroid treatment, and possibly latent neuromuscular abnormality revealed by RNST, may have an impact on the risk of developing generalized disease in Korean patients presenting with ocular myasthenia.     

眼肌型重症肌无力临床分析

目的总结分析眼肌型重症肌无力患者的临床特征,以为诊断和治疗提供参考依据。方法回顾性分析113例眼肌型重症肌无力患者的临床资料。采用免疫荧光细胞染色方法检测血清乙酰胆碱受体（AChR）抗体和肌肉特异性受体酪氨酸激酶（MuSK）抗体表达水平,分析这两项免疫学指标对眼肌型重症肌无力向全身型转化的预测价值。结果成年发病的眼肌型重症肌无力好发于40岁以上男性,多以眼睑下垂（95例,84．07％）为首发症状,少数以复视（18例,15．93％）起病。疲劳试验和新斯的明试验阳性率分别为79．44％（85／107）和84．85％（84／99）．低频重复神经电刺激和血清甲状腺抗体异常率分别为44．32％（39／88）和28％（14／50）,胸腺增生和胸腺瘤阳性率分别为16．67％（17／102）和11．76％（12／102）;血清AChR抗体阳性率为62.83％（71／113）;但MuSK抗体均呈阴性。眼肌型重症肌无力向全身型转化率为12．39％（14／113）,其中血清AChR抗体强阳性者（13例,28．26％）显著高于弱阳性者（1例,4％）,二者差异有统计学意义（X^2=4．587,P=0．032）。结论成年发病的眼肌型重症肌无力好发于中年以上男性,主要表现为眼睑下垂和复视,大多数患者伴发胸腺和甲状腺异常。血清AChR抗体表达水平升高预示向全身型转化率升高,鲜有MuSK抗体阳性反应。     

The effect of prednisone on the progression from ocular to generalized myasthenia gravis

Fifty percent of ocular myasthenia gravis (OMG) patients will progress to generalized myasthenia, 90% within 3 years from the onset of ocular symptoms. This study was performed to determine whether treatment with oral prednisone initiated and completed within 2 years from the onset of ocular symptoms would affect the progression of ocular myasthenia to generalized myasthenia gravis (GMG). Fifty-six patients were included in this review, with 27 patients in the prednisone-treated group and 29 patients in the untreated group. The treated group was initiated on 60 mg of prednisone daily with a slow taper over 3-6 months. At 2 years, significantly fewer patients in the treated group (3 of 27) progressed to generalized myasthenia when compared to the untreated group (10 of 29) (chi(2), p=0.04). Our results suggest that the early use of steroids may decrease progression of ocular to generalized myasthenia gravis. The decision to use steroids should be considered early in the course of patients diagnosed with ocular myasthenia gravis. This study should be considered preliminary and a prospective trial is warranted to confirm our observations.     

Ocular aspects of myasthenia gravis

Ocular myasthenia gravis is a not uncommon autoimmune disorder causing diplopia, ptosis, and weakness of lid closure. The predilection of myasthenia for the ocular muscles may be related to differences between limb and extraocular muscles in either physiological function or antigenicity. Clinically, ocular myasthenia can mimic any form of pupil-sparing ocular motility disorder. Dynamic abnormalities of myasthenic eye movements may reflect the primary hallmarks of the disease, which are fatigability and variability in strength, or secondary adaptive effects by the central nervous system. Tests to confirm the diagnosis include edrophonium challenge, repetitive nerve stimulation, single-fiber electromyography (EMG) of the frontalis, and assays for antibody directed against the acetylcholine receptor: all are less sensitive for ocular myasthenia than for generalized myasthenia. There is a higher incidence of other autoimmune conditions in myasthenia, notably thymoma and thyroid dysfunction. The differential diagnosis includes other diseases of the neuromuscular junction, such as Lambert-Eaton syndrome and botulism. Treatment consists of symptomatic use of acetylcholinesterase inhibitors and immunosuppression with steroids or azathioprine. Between 50 and 70% of patients with ocular myasthenia will eventually develop generalized disease: there is some retrospective data that steroids or azathioprine may reduce this by about 75%. The role of thymectomy in ocular myasthenia remains unclear.     

Acetylcholine receptor antibodies in myasthenia gravis

A multivariate statistical analysis of levels of serum acetylcholine receptor antibody (AChR Ab) obtained from 197 patients with various clinical forms of myasthenia gravis (MG) was performed. Elevated AChR Ab levels are specific for MG, but normal AChR Ab levels do not rule out MG. Patients in remission or with purely ocular MG had the lowest incidence of elevation of serum AChR Ab levels, while patients with generalized, severe MG, particularly in the presence of thymoma, tended to have the greatest antibody elevations. Corticosteroids depressed AChR Ab levels, but thymectomy did not exert a consistent effect on antibody levels within a 24- to 30-month postoperative period. The relatively low 55% positivity of antibody elevations in all 197 patients probably reflects the use of heterologous (rat) AChR.     

Heterogeneity in myasthenia gravis: HLA phenotypes and autoantibody responses in ocular and generalized types

HLA phenotypes and autoantibody responses were studied in 71 Japanese patients with myasthenia gravis. HLA-A2, Bw61, and DRw9 were associated with ocular myasthenia gravis (corrected p [CP] less than 0.05 relative risk [RR] = 2.88; CP less than 0.02, RR = 3.60; and CP less than 0.001, RR = 4.63, respectively) and HLA-DRw8 was associated with generalized myasthenia gravis (CP less than 0.001, RR = 5.40). Neither HLA-B8 nor DR3 was found in Japanese patients. The titer of antiacetylcholine receptor antibody (AChR Ab) and the incidence of autoantibodies other than AChR Ab were higher in patients with generalized myasthenia gravis than in those with the ocular type (2.77 +/- 0.62 versus 0.17 +/- 0.03 pmol/ml, p less than 0.001; and 60.6 versus 29.0%, p less than 0.02, respectively). Patients with a high titer of AChR Ab or with autoantibodies had an increased frequency of HLA-DRw8 (CP less than 0.02, RR = 4.61, and CP less than 0.005, RR = 4.53, respectively); whereas patients with a low titer of AChR Ab or without autoantibodies had an increased frequency of HLA-DRw9 (CP less than 0.001, RR = 8.26, and CP less than 0.005, RR = 4.08, respectively). These findings suggest that ocular and generalized myasthenia gravis might have different immunogenetic backgrounds.     

HLA antigens and acetylcholine receptor antibody in the subclassification of myasthenia gravis in Hong Kong Chinese.

Thirty seven Chinese adults and 23 children in Hong Kong with myasthenia gravis were tested for HLA-A and -B antigens and acetylcholine receptor (AChR) antibody. HLA BW46 had a significantly increased prevalence in patients with juvenile onset ocular myasthenia gravis. Only one third of the juvenile ocular patients had AChR antibodies and the titres were generally low. In the adult patients taken as a whole there was a non-significant increase in the prevalence of HLA B5 and HLA B15. HLA BW46 was more prevalent in adult patients without AChR antibody and less prevalent in patients with AChR antibody but the findings were not statistically significant. It is suggested that ocular myasthenia gravis is determined by a pathological mechanism for which susceptibility is determined by HLA BW46. There was a strong correlation between ocular myasthenia gravis and Graves' disease in the adult patients. The possibility that ocular myasthenia gravis is accentuated by a BW46-associated predisposition to ocular Graves' disease is considered.     

Ocular myasthenia: diagnosis and treatment

Myasthenia gravis is a rare, auto-immune disorder of the neuromuscular junction. Onset signs frequently involve ocular muscles, accounting for ptosis and/or diplopia in more than 75% of cases. Among the cases with purely ocular muscle involvement, less than one half will never progress towards a more general form of myasthenia. However, even if they do not share the potentially life-threatening course of generalized myasthenia, purely ocular forms are often responsible for severe impairment in everyday life. The diagnosis is essentially based on fluctuations in the time and topography of the ocular muscle weakness. It still remains uneasy, as investigations such as electromyography, search for antiacetycholine receptor antibodies (positive in 50% of cases of purely ocular myasthenia), and edrophonium chloride test sometimes yield false negative results. Whereas some patients get better while on anticholinesterasic drugs alone, most of them will experience insufficient improvement and need steroids and/or immunosuppressant drugs. There is no indication for plasma exchanges, intravenous immunoglobulin or thymectomy (except in the presence of thymoma). This treatment could well decrease the risk of an evolution towards generalized myasthenia. The reasons underlying the vulnerability of ocular motor muscles in myasthenia are complex and several factors (linked to immunology, anatomy and function) may combine to bring about their specific involvement. In the future, randomized, controlled trials will be necessary, in order to determine a more rational approach of the treatment of ocular myasthenia, which currently lies mostly on retrospective data and the expertise of reference centers implicated in the management of the disease.     

Myasthenia gravis in Ceará, Brazil: clinical and epidemiological aspects

A retrospective chart review was performed on patients diagnosed as having myasthenia gravis in Ceará State, Brazil and who were followed from October 1981 to June 2009. Clinical and epidemiologic aspects were evaluated. In this work, 122 patients were studied, of whom 85 (69.7%) were females and 37 (30.3%) were males. The disease duration ranged from five months to 50 years (8.9±8.1 years). Age at the first symptoms varied from 0 to 74 years (31.9±14.4 years). The first main symptoms and signs were ptosis, diplopia and limb weakness. Generalized myasthenia was the most common clinical presentation, but 5.1% (n=6) persisted as ocular myasthenia. Thymectomy was performed in 42.6% (n=52) of myasthenic patients. A thymoma was present in 10 patients. Serum acetylcholine receptor (AChR) antibodies were present in 80% (n=20) of specimens tested. The data presented are similar to those of studies performed in other countries.     

A study of myasthenia gravis in patients with and without thymoma

This study was undertaken to compare the clinical, neurophysiological, radiological and prognostic features of myasthenia gravis with and without thymoma. 37 patients with myasthenia gravis (27 males, 10 females), with age range of 4.5 to 72 (mean 39) years, were managed at a tertiary care centre in India. Four patients were below 15 years of age and 6 above 55 years. Most of the patients were in stage II (34). There were 2 patients in stage III and 1 in stage I. 27 patients underwent thymectomy. Thymoma was detected in 10 cases. The decrement in patients with thymoma ranged between 11 and 62% (mean 27.9%) and nonthymoma group 10-75% (mean 28%). CT scan of thorax revealed mediastinal mass in 5 out of 10 cases of thymoma and 2 out of 27 patients without thymoma. Outcome of myasthenia gravis with thymoma was worse than without thymoma at 1 year followup. Severity of illness, extent of decrement, lack of facilitation, duration of illness and age of the patients were not related to the outcome. It is concluded the clinical and neurophysiological changes in myasthenia gravis with and without thymoma do not differ. However, patients with thymoma have a worse outcome.     

Enzyme-linked immunosorbent assay for antibody against the nicotinic acetylcholine receptor in human myasthenia gravis

Antibody against acetylcholine receptor (AChR) of human skeletal muscle was measured using enzyme-linked immunosorbent assay and found in 23 (74%) of 31 Japanese patients with generalized myasthenia gravis. In 15 patients with generalized myasthenia gravis who had not undergone thymectomy and who were not receiving adrenocorticosteroids, the antibody was found in 13 (87%). Antibody was also found in 13 (54%) of 24 patients with myasthenia gravis against AChR fractions obtained from fetal calf thymus. Based on the subunit structures of the AChR protein, the double precipitation assay using iodine 125-alpha-bungarotoxin is also capable of detecting antibody against the toxin binding site, by cross reactivity. This is among the first reports of experiments in which enzyme-linked immunosorbent assay was used to measure the antibodies in human myasthenia gravis and provides evidence of anti-AChR antibody against antigens from fetal calf thymus.     

Seronegative myasthenia gravis

Of 221 patients with myasthenia gravis, 18.5% had no detectable antibodies to acetylcholine receptor. Seven of 14 patients (50%) with only ocular symptoms for more than 2 years were seronegative, and 25 of 145 (17%) patients with generalized myasthenia were seronegative. The clinical characteristics of seronegative patients did not differ from patients with high antibody titers. No seronegative patient had a thymoma, but that difference did not reach statistical significance. Lack of serum antibodies did not preclude favorable response to thymectomy or plasmapheresis.     

Anti-neuroblastoma antibodies in myasthenia gravis: clinical and immunological correlations

Forty-four of 109 myasthenia gravis (MG) patients (40%) had serum antibodies against human neuroblastoma cells (NBL). Anti-NBL antibodies were most frequent in the sera of MG patients who had either a hyperplastic thymus or a thymoma, clinically mild to moderately severe generalized MG, and a long disease duration (greater than or equal to 11 years). No correlation between individual anti-NBL antibody and anti-acetylcholine receptor (AChR) antibody titers was observed. Seven of the 19 patients negative for anti-AChR antibodies (37%) had anti-NBL antibodies in their sera. These findings provide further evidence for immunological heterogeneity in MG. In addition to the typical autoantibodies to the AChR, autoimmunization against neural antigens can frequently be detected in these patients.     

Spontaneous remission in juvenile myasthenia gravis: A cohort of 13 cases and review of the literature

We describe the clinical course of patients with juvenile myasthenia gravis who experienced spontaneous remission and review the literature. This is a retrospective study of 13 patients with spontaneous remission from a cohort of 133 patients younger than 18-years-old. We compared several variables with potential prognostic value in patients with and without spontaneous remission. Ten percent of patients (13/133) experienced spontaneous remission. There was no difference in age at onset or sex compared to the overall JMG population. Spontaneous remission occurred in 2/40 (5.0%; 95% CI: 0.6–16.9) patients in Class I (ocular); in 11/53 (20.8%; 95% CI: 10.8–34.1) patients in Class II-III (mild, moderate, generalized) (p < 0.0018) and in 0/40 patients in Class IV-V (severe, needs intubation). Of the AChR antibody positive patients, 10/97 (10.3%; 95% CI: 5.0–18.1) had spontaneous remission, compared with 2/29 (6.9%; 95% CI: 0.9–22.8) of those without AChR antibodies (p = 0.583). Strikingly, none of the 36 patients with thyroid antibodies had spontaneous remission compared with 13/58 (22.4%) of those without thyroid antibodies (95% CI: 7.3–21.8; p < 0.001). Ten percent of patients with juvenile myasthenia gravis achieved spontaneous remission, mainly in those with Class II-III disease and no associated thyroid antibodies.     

眼肌型重症肌无力进展为全身型重症肌无力的临床相关因素分析

目的 :探讨眼肌型重症肌无力进展为全身型重症肌无力的临床相关预测因素。方法 :33例初诊为眼肌型重症肌无力的患者经过3年随访,根据疾病进展结局分为眼肌型重症肌无力组(13例)和进展为全身型重症肌无力组(20例)。对与疾病进展可能相关的临床因素进行分析。结果 :进展为全身型重症肌无力组患者初诊时的定量重症肌无力评分、乙酰胆碱受体抗体阳性率、抗核抗体阳性率、合并胸腺瘤的比例以及合并糖尿病的比例均高于眼肌型重症肌无力组(P值均0.05)。结论 :定量重症肌无力评分高、乙酰胆碱受体抗体阳性、抗核抗体阳性以及合并胸腺瘤和糖尿病可能是眼肌型重症肌无力进展为全身型重症肌无力的预测指标。     

Thymectomy in the treatment of myasthenia gravis: report of 247 patients

Summary We made a retrospective assessment of the long-term outcome in 247 consecutive patients with myasthenia gravis (MG) who underwent thymectomy in the period January 1971–December 1985. In 84 cases a thymoma was found at surgery, while 163 patients had a non-neoplastic thymus. The duration of symptoms before surgery, the age at onset of the disease and the presence of germinal centres in the thymus did not appear to influence the prognosis. Patients with a non-neoplastic thymus showed a better response to thymectomy. Thymoma was associated with more severe disease and with a higher mortality; moreover, more thymoma patients required corticosteroid treatment in order to achieve good therapeutic results. In our opinion, thymectomy is indicated in the treatment of generalized MG, while ocular myasthenia seems not to be improved by the removal of the thymus.     

Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients

One hundred consecutive patients with myasthenia gravis (MG) referred between 1985 and 1989 were analysed for epidemiological characteristics, evolution of early signs, delay in diagnosis, yield of diagnostic tests and effects of treatment. The female to male ratio was 1.6:1.0. Sixteen patients had a thymoma. Ocular MG occurred in 14. Associated autoimmune diseases were found in 15 patients. In 34% of the women and 10% of the men the diagnosis was delayed for more than 2 years. In the first 3 months progression was more rapid in men than in women. Anti-acetylcholine receptor antibodies were found in 94% of the patients with generalized MG and in 29% of the ocular patients. The neostigmine or the edrophonium test was positive in 84% of the generalized and in 60% of the ocular patients. Electromyography was diagnostic in 71% of the generalized and in 42% of the ocular patients tested. Thymectomy was performed in 56 patients (12 with thymomas). Fifty-one per cent were treated with one or more immunosuppressive drugs, at any time. After a mean follow-up of 9.6 years after onset remissions had occurred in 43%, considerable improvement in 25%, moderate improvement in 20% and 12% remained unchanged. There were no deaths due to MG. Thirty-six per cent remained dependent on immunosuppressive drugs. Medication-free remission was most frequent (35%) in the early-onset (< 50 years) group. Side-effects of pyridostigmine were noted in 34% of 99 patients, of prednisone in 65% of 49 patients, and of azathioprine in 54% of 28 patients, but these necessitated stopping the drug in only 1%, 10% and 14% respectively. Received: 18 March 1996 Received in revised form: 24 June 1996 Accepted: 9 September 1996     

Muscle autoantibodies in subgroups of myasthenia gravis patients

Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR), but several other muscle autoantibodies have also been identified in patient sera. We studied muscle autoantibodies against AChR, striated muscle tissue sections (SH), titin, citric acid antigen (CA), and ryanodine receptor (RyR) in sera from 146 consecutive MG patients to evaluate whether a single test or several tests together can predict a thymoma. The MG patients were divided into five subgroups; ocular MG, early-onset MG (< 50 years), late-onset MG (≥ 50 years), MG with thymoma, and AChR antibody negative MG. AChR, SH, titin, CA, and RyR antibodies were detected in 85%, 34%, 34%, 25%, and 14% of the MG patients, respectively. For thymoma MG, AChR, SH, titin, CA, and RyR antibodies were detected in 100%, 75%, 95%, 70%, and 70% respectively. SH, titin, CA, RyR antibodies, and computed tomography of the anterior mediastinum have similar sensitivity for thymoma MG. The specificity of RyR, titin, CA, and SH antibodies for thymoma was 70%, 39%, 38%, and 31%, respectively, which is significantly higher for RyR antibodies than for the others. No single muscle antibody assay can predict a thymoma, and a combination of several antibody assays is preferred, although RyR antibody testing alone showed 70% sensitivity and specificity for thymoma MG. SH and CA antibodies provided only little additional information. Received: 23 September 1999, Received in revised form: 6 December 1999, Accepted: 19 January 2000